van der Bent A, Blommaert A G, Melman C T, IJzerman A P, van Wijngaarden I, Soudijn W
Division of Medicinal Chemistry, Center for Bio-Pharmaceutical Sciences, Leiden, The Netherlands.
J Med Chem. 1992 Mar 20;35(6):1042-9. doi: 10.1021/jm00084a009.
A series of novel nonpeptide cholecystokinin-A (CCK-A) antagonists have been synthesized. Designed on the basis of the structural homology between lorglumide and L-364,718, as investigated with molecular modeling, these compounds constitute a link between the N-acylglutamic acid and 3-amino-5-phenyl-1,4-benzodiazepin-2-one derived antagonists. The prepared compounds were tested in vitro as antagonists of the binding of [3H]-(+/-)-L-364,718 and [3H]-CCK-8(S) to rat pancreas and guinea pig brain membranes, respectively. All compounds proved to be selective for the (peripheral) CCK-A receptor, the most potent analogue, 6, having a Ki value of 90 nM. The structure-activity profile of the series of hybrid compounds relates closest to that of the N-acylglutamic acid derived antagonists.
一系列新型非肽类胆囊收缩素-A（CCK-A）拮抗剂已被合成。基于洛谷胺和L-364,718之间的结构同源性设计，并通过分子建模进行研究，这些化合物构成了N-酰基谷氨酸和3-氨基-5-苯基-1,4-苯并二氮杂卓-2-酮衍生拮抗剂之间的联系。所制备的化合物分别作为[3H]-(+/-)-L-364,718和[3H]-CCK-8(S)与大鼠胰腺和豚鼠脑膜结合的拮抗剂进行体外测试。所有化合物均被证明对（外周）CCK-A受体具有选择性，最有效的类似物6的Ki值为90 nM。该系列杂合化合物的构效关系与N-酰基谷氨酸衍生拮抗剂的构效关系最为接近。
